Sodium ion entry into endothelial cells through Na+/K+/2CI- channels was studied during NaCI hyperosmolarity associated with intestinal nutrient absorption. As sodium enters the cell, it is removed in exchange for calcium ions by the sodium/calcium exchanger. The increase in calcium is associated with a large increase in nitric oxide (NO) concentration. The linkage of sodium ions to NO production raised the possibility of a sodium leakage when oxygen availability is decreased and the concentration of NO increases. Pilot studies of intestinal and cerebral arterioles indicate that when oxygen tension at the arteriolar wall is decreased by as little as ~5 mmHg, sodium ions enter cells to activate the Na/Ca exchanger and increase NO formation. This may be a sensitive mechanism to couple local oxygen tension to NO generation in the microvasculature. Determining which sodium channels are oxygen sensitive in the in vivo and in vitro state in the intestinal and cerebral arterioles may reveal a rapid means for endothelial cells to regulate NO production in response to oxygen. As the endothelial cells are producing NO, pilot data indicate the arginine for the NO production is provided by the cationic amino acid transporter-1 (CAT-1). Providing additional arginine increases in vivo NO production within 10 seconds and suppression of arginine transport with the competitor lysine decreases NO within 5 seconds. Studies are needed to determine whether CAT-1 transport of arginine or use of arginine from intracellular stores is the dominate source for NO production when endothelial cells are stimulated to increase NO production. Once the NO is produced in the walls of small arteries and larger arterioles, it may enter the blood to be carried to distal smaller arterioles. This mechanism may allow large intestinal and cerebral arterioles to communicate with smaller arterioles by hemoglobin carriage of NO. A substantial fraction of the NO in blood may be from NO loading in the small arteries based on their very high wall NO concentration and represents a new form of vascular regulation.